The objectives of this proposal are based on a series of findings generated in Dr. Thiele's laboratory. Specifically, dipeptidyl- peptidase I (DPPI) has been found to be expressed in high levels in the specialized granules of T cells, natural killer cells and cells of myeloid lineage where DPPI plays a requisite role in post- translational processing and activation of granule serine proteases. Moreover, depletion of DPPI enriched cells by the lysomotropic agent L-leucyl-L-Leucine methyl ester (Leu-Leu-OMe) has been observed to favorably modulate the course of acute GVHD and skin allograft rejection. The specific aims of the present proposal are to determine the stage in T cell development at which DPPI is expressed, determine the inducibility of DPPI expression and CTL effector function in Leu- Leu-OMe resistant, DPPI deficient T cell subsets following alloantigenic stimulation in vitro or in vivo, and assess effector function of Leu-Leu-OMe resistant, DPPI deficient T cell subsets. These specific aims will determine the nature of differentiation and activation events leading to DPPI expression and assess subsets of Leu-Leu-OMe resistant, DPPI deficient T cells. Clinically, these studies are important as further characterization and differentiation of cytolytic effector function could eventually lead to more selective pharmacological modification of CTL responses in human diseases.